Trimethylsilyl triflate → 2-Bromo-5,6-dichloro-1-(5-deoxy-2,3-di-O-acetyl-beta-D-ribofuranosyl)benzimidazole

HRID 2227221Notes

Reaction equation

HRID 2227221 reaction equation
[Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[CH:17]1[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Br:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH3:30])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1

Participants

6

Reactant 3

HCID 65367Trimethylsilyl triflateHCID 4660172-bromo-5,6-dichloro-1H-benzimidazoleHCID 11196237Tri-O-acetyl-5-deoxy-D-ribofuranose

Product 1

HCID 699962602-Bromo-5,6-dichloro-1-(5-deoxy-2,3-di-O-acetyl-beta-D-ribofuranosyl)benzimidazoleYield 53%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a stirred suspension of 2-bromo-5,6-dichlorobenzimidazole (which may be made according to U.S. Pat. No. 5,248,672) (1b, 1.33 g, 5 mmol) in dry MeCN (25 ml) was added 1.8 ml (7.5 mmol) of BSA. The reaction mixture was stirred at room temperature for 15 min to give a clear solution. This solution was treated with a solution of 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (1.4 g, 5.5 mmol) in dry acetonitrile (5 mL) and 1.3 mL (6.5 mmol) of TMSOTf at room temperature for 30 min. A fresh solution of 5-deoxy-1,2,3-tri-O-acetyl-D-fibofuranose (0.26 g, 1 mmol) in dry MeCn (2 mL) was added and stirring was continued at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc (100 mL). The EtOAc solution was washed with a sat. NaHCO3 solution (100 mL×2), dried (Na2SO4), and evaporated. The residue was recrystallized from MeOH to give 1.2 g (53%) of 2b as white crystals. The mother liquor was evaporated and the residue was chromatographed on a silica column (2.2×35 cm, eluted with CHCl3). Evaporation of fractions 16-42 (20 mL per fraction) and recrystallization from MeOH gave an additional 0.6 g (27%) of 2b as white crystals. The total yield of 2b was 1.86 g (80%). MP: 145-148° C. HRMS: (EI, with DCI probe) m/z 463.9582 (6%, M+=463.9541). 1H NMR (DMSO-d6): 8.11 (s, 1, 7-H), 7.99 (s, 1, 4-H), 6.14 (d, 1, 1′-H, J1′-2′=6.5 Hz), 5.65 (t, 1, 2′-H, J2′-3′=7.0 Hz), 5.27 (dd, 1, 3′-H, J3′-4′=5.5 Hz), 4.25 (m, 1, 4′-H, J4′-5′=6.5 Hz), 2.13, 2.02 (2×s, 6, 2×Ac), 1.51 (d, 3, 5′-H). 13C NMR (DMSO-d6): δ169.61, 168.20, (2×COCH3), 142.28 (C3a), 132.80 (C7A), 131.49 (C2),126.35, 126.07 (C5 and C6), 120.22 (C4),113.37 (C7), 87.93 (C1′), 77.98 (C4′), 72.89 (C3′), 70.91 (C2′), 20.33, 20.07 (2×COCH3), 17.78 (C5′). Anal. (C16H15BrCl2N2O5) C, H, N. Evaporation of fractions 45-58 gave 0.38 g of 3b which was further purified on a silica column (2.2×8 cm, eluted with hexane, 30% EtOAc/hexane). Evaporation of fractions 9-12 (20 mL per fraction) gave 0.26 g (11 %) of 3b as a colorless syrup. HRMS: (EI) m/z 463.9529 (2%, M+=463.9541). 1H NMR (DMSO-dhd 6): δ7.95 (s,1, 4-H), 7.89 (s, 1, 7-H), 6.68 (d, 1, 1′-H,J1′-2′−4.5 Hz), 5.70 (t, 1, 2′-H, J2′-3′=5.0 Hz), 5.28 (dd, 1, 3′-H, J3′-4′=7.0 Hz), 4.72 (m, 1, 4′-H, J4′-5′=6.5 Hz), 2.03, 1.51 (2×s, 6, 2×Ac), 1.39 (d, 3, 5′-H). 13C NMR (DMSO-d6): δ169.46, 168.30, (2×COCH3), 142.13 (C3a), 133.58 (C7a), 131.10 (C2), 125.74, 125.42 (C5 and C6), 119.95 (C4), 114.24 (C7), 86.87 (C1′), 76.89 (C4′), 74.55 (C3′), 71.18 (C2′), 20.21, 19.58 (2×COCH3), 18.12 (C5′).

Workup

  1. customto give a clear solution
  2. additionA fresh solution of 5-deoxy-1,2,3-tri-O-acetyl-D-fibofuranose (0.26 g, 1 mmol) in dry MeCn (2 mL) was added
  3. stirringstirring
  4. waitwas continued at room temperature for 30 minutes
  5. washThe EtOAc solution was washed with a sat. NaHCO3 solution (100 mL×2)
  6. dry with materialdried (Na2SO4)
  7. customevaporated
  8. customThe residue was recrystallized from MeOH

Sources & evidence

ORD record
ord-f9a24d4779cd44388682f98a975bda7d
Source dataset
uspto-grants-2002_07
Patent number
US06413938B1

Reaction notes

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